The transmission of HIV-1 by both sexual and parenteral routes makes it likely that a successful preventative vaccine against this virus will need to induce protective immunity in both mucosal and systemic compartments. Moreover, aside from attenuated live virus vaccines, candidate HIV-1 vaccines usually require a prime-boost immunization strategy to elicit the broadest immune responses. The need to induce both mucosal and systemic immunity using a prime-boost protocol provides the rationale for our HIV-1 vaccine development program. The long-term objective of this program is to develop an HIV-1 vaccine that elicits protective immunity in both the mucosal and systemic compartments. This objective is pursued via two goals. The primary goal is to evaluate the safety and immunogenicity of an oral Salmonella HIV-1 gp120 DNA vaccine vector in health human volunteers. This goal stems from a long-standing collaboration of our group to develop Salmonella as a mucosal delivery system for HIV-1 antigens. To our knowledge, this will be the first study in volunteers to use an intracellular bacterium to deliver a DNA vaccine mucosally. The secondary goal is to develop an Env immunogen that elicits a broader spectrum of neutralizing antibodies than gp120 which can be delivered by Salmonella typhi as a DNA vaccine and as a soluble protein immunogen. Accordingly, we will evaluate the safety and immunogenicity of a new single chain chimeric protein, scgp120/Ba-L- CD4, that is predicted to elicit broadly neutralizing antibodies due to the constitutive exposure of conserved epitopes in the co-receptor binding domain of gp120. In this immunogen proves safe in preclinical studies in animals, it will be evaluated in human volunteers both as a soluble subunit protein and formulated as a DNA vaccine delivered by attenuated Salmonella as a vaccine vector for DNA vaccines encoding gp120Ba-L and scgp120Ba-L-CD4. Project 2 will carry out Phase I clinical trials in volunteers of these immunogens based on the preclinical data obtained in Projects 1 and 2. These projects will be supported by an Administrative Core.